childhood acute myeloid leukemia in mice with severe combined

RAPID COMMUNICATION

Childhood Acute Myeloid Leukemia in Mice With Severe Combined Immunodeficiency

By Lisa M. Chelstrom, Roland Gunther, John Simon, Susanna C. Raimondi, Robert Krance, William M, Crist, and Fatih M. Uckun

Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(l6j AML, and 2 children with t(9;ll) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SClD mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(821) AML patients and 4 of 6 inv(l6) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was de-

CUTE MYELOID LEUKEMIA (AML) is a heteroge- neous group of diseases that accounts for 20% to 25%

of acute childhood leukemias.”’ During the last decade, im- provement in the overall cure rate for children with AML has been less striking than for children with acute lymphoblastic leukemia (ALL).6-9 The study of new forms of therapy for AML has been hampered by the lack of suitable experimental models. Therefore, we sought to establish an in vivo model system that could replicate human childhood AML.

In this report, we provide evidence that (1) leukemic blasts from a majority of newly diagnosed inv(l6) AML patients cause disseminated human leukemia in mice with severe combined immunodeficiency (SCID), and ( 2 ) the SCID mouse thymic microenvironment preferentially supports the

A

From the Departments of Therapeutic Radiology-Radiation On- cology, Pediatrics, Laboratory Medicine, and Pathology, University of Minnesota, Minneapolis; the Departmenis of Hematology/Oncol- ogy, Pathology, and Tumor Cell Biology, St Jude Children’s Re- search Hospital; and the University of Tennessee, College of Medi- cine, Memphis.

Submitted March 5, 1994; accepted April 13, 1994. Supported in part by US Public Health Service Grants No. R01

21737, CA-21745 (CORE), CA-30969, CA-05587, CA-31544, and CA-15525 from the National Cancer Institute, Department of Health and Human Services, and special grants from the Minnesota Medical Foundation, ChildrenS Cancer Research Fund, and Bone Marrow Transplant Research Fund, University of Minnesota, National Child- hood Cancer Foundation (NCCF), and the American Lebanese Syr- ian Associated Charities (ALSAC). F.M. U. is a Scholar of the Leuke- mia Society of America. This is publication #l40 from the Tumor Immunology Laboratory, University of Minne.yota.

Address reprint requests to Fatih M. Uckun, MD, PhD, Box 356 UMHC, University of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. section 1734 solely to indicate this fact.

CA-42433, R01 CA-441 14, R01 CA-51425, R01 CA 421 1 1 , PO1 CA-

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20

pendent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SClD mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, espe- cially inv(l6) AML, can cause disseminated human leukemia in SClD mice without exogenous cytokine support. The SClD mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML. 0 1994 by The American Society of Hematology.

in vivo survival and growth of AML blasts. This SCID mouse model system may facilitate the development of more successful therapy in childhood AML.

MATERIALS AND METHODS

Leukemic cells. Specimens for this study were obtained by rou- tine diagnostic bone marrow (BM) aspirates from 12 children with newly diagnosed de novo AML referred to St Jude Cluldren’s Re- search Hospital (Memphis, TN). Highly blast-enriched mononuclear cell fractions containing greater than 90% leukemic cells were isolated by Ficoll Hypaque (Pharmacia, Piscataway, NJ) density gradi- ent separation. Table l summarizes the characteristics of patients whose BM specimens were used in the present study. The karyotype of leukemic blasts were determined in all patients at the time of diagnosis according to previously published methods3 Cytogenetic analyses identified a t(8;21)(q22;q22) translocation in 4 cases, an inv(16)(p13q22) in 6 cases, and a t(9; 1 l)(p21;q23) in 2 cases. In- formed consent for laboratory studies was obtained from parents, patients, or both based on Department of Health and Human Services guidelines. The diagnosis of AML was based on French-American- British riter ria.^

SCID mice. All SCID mice (N = 27; age: 6 weeks) were produced by specific pathogen-free CB-l7 scidscid breeders and main- tained in a specific pathogen-free environment in Micro-Iso- lator cages (Lab Products, Inc, Maywood, NY), as previously reported.“”* One day after 2-Gy total body irradiation, mice were inoculated with leukemic cells either intravenously (1V) via tail-vein injections or operatively via implantation under the kidney capsule. Mice were hlled at 17 to 19 (median = 18.5) weeks, unless they died earlier. Mice were necropsied at the time of killing, and histopathology, flow cytometry, and polymerase chain reaction (PCR) analyses were performed to assess their burden of human leukemic cells, as previously reported.“”* MY7(anti-CD13)-phycoerythrin (PE), 9.4(anti-CD45)-fluorescein isothiocyanate (FITC), and MY9(anti- CD33)-FITC were used to identify human AML cells in multipa- rameter flow cytometric analyses, as Human DNA was detected by amplifying a 110-bp fragment from the first exon of the human &globin gene using two 20-base oligonucleotide primers, PC03 and PCO4, that flank the region to be amplified, as previously described in detail.'"^''

RESULTS AND DISCUSSION

We and others have used mutant CB. 17 mice with severe combined immunodeficiency as a model system to examine

Blood, VOI 84, NO 1 (July l) . 1994: PP 20-26

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HUMAN AML IN SClD MICE 21

Table 1. Patient Characteristics

Overt Leukemia

Age Sex Auer Rods WBC Hgb Plt CNS in SClD UPN Diagnosis (vrs) (ME) FAB in Blasts (xlO9/L) (g/dL) (xlO9/L) Leukemia Mice

1 t(8;21)AML 6.8 F M2 + 52.9 5.9 20 - -

2 t(8;21)AML 7.3 F M2 + 9.1 7.0 20 - -

3 t(8;21)AML 13.3 M M2 + 14.7 7.4 14 - -

4 t(8;21)AML 14.0 F M2 - 109.2 7.7 126 + + 5 inv(l6)AML 11.6 F M4 - 31.3 4.5 23

7 inv(l6)AML 14.5 M M4 + 401.0 11.6 56 + +

9 inv(l6)AML 7.5 M M4 - 50.5 7.6 32 + -

10 inv(l6)AML 14.6 F M4 - 249.0 8.2 9 + + 11 t(9; 11)AML 6.4 M M5 - 47.0 8.6 66 12 t(9; 11 )AML 3.2 M M5 - 23.5 9.6 145

- + 6 inv(l6)AML 16.0 M M5 - 13.0 9.4 58 - -

8 inv(l6)AML 9.8 F M4 + 104.0 3.6 20 - +

- -

- -

Abbreviations: UPN, unique patient number; FAB, French-American-British; WBC, white blood cell count: Hgb, hemoglobin; Plt, platelets; CNS, central nervous system.

Table 2. Infiltration of SClD Mice Organs by Primary Leukemia Cells From Children With Newly Diagnosed AML -~

SClD No. of Cells Histopathology Mouse Inoculated

UPN No. ( ~ 1 0 ~ ) BM SPL LIV BR KD LU HRT OV THY GI

1 2368 2371 2374

2 2308 2383 2397

3 2382 4 2494

2488 5 2493

2483 6 2496

2490 2491

7 2390 2387

8 2497 2487

9 2495 2485

10 2389 11 2307

2373 2375

12 2492 2480 2481

- +* - + NE - - +* ND

-

NE + -

NE

-

NE NE

NE NE

NE NE +

ND - NE NE NE + NE NE NE NE NE

NE +* + NE +* NE + + +* NE + + + NE +* ND +* +* NE + +* NE +* NE + NE NE

BM SPL LIV BR THY

+ + + + + + - + + NE

- + NE - -

+ + + + + + - + + + + + + + N E + + - + + + + - + + + + + + + + + + + + + + + + + + - + + N E + + + + + + + + + N E + + NE + NE + ND ND ND ND + - + + + + + + - + + + + + N E + + + + + + + + + + + + + + + + + + + + + + + + + + + + C +

+ + + + N E + + + + N E

Sublethally irradiated (200 cGy) SClD mice were inoculated with cryopreserved primary BM blasts from children with newly diagnosed de novo AML as discussed in Materials and Methods. The site of inoculation (ie, IV or under the kidney capsule [KDI) is indicated in parentheses. UPN 1-4 had t(8;21) AML, UPN 5-10 had invil6) AML, and UPN 11-12 had t(9;ll) AML. SClD mouse no. 2387 could not be necropsied on the day of death because of staffing problems. Therefore, only BM of this mouse was examined for the presence of human AML cells.

Abbreviations: NE, not examined; ND, not determined; SPL, spleen; LIV, liver; BR, brain; KD, kidney; OV, ovary; LU, lungs; HRT, heart; THY, thymus; GI, gastrointestine (stomach and gut).

* Indicates that the particular organ is enlarged.




22 CHELSTROM ET AL

the in vivo homing, engraftment, and growth patterns of normal and malignant human hematopoietic cells."~" In the present study, we used the SClD mouse model system to examine the in vivo engraftment and proliferation of primary leukemic cells from 4 children with t(8;21) AML, 6 children with inv( 16) AML, and 2 children with t(9; 1 1 ) AML.

When injected IV into SClD mice, leukemic cells from all patients were able to engraft and proliferate in SClD mouse thymus (Table 2). At necropsy, 8 (SCID mouse nos. 2371, 2383, 2488, 2390. 2497, 2487, 2389, and 2373 in Table 2) of 16 thymuses examined were found to be mark- edly enlarged. Histopathologically, AML cells were closely packed in dense sheets that effaced the normal architecture

Fig 1. Infiltration of SClD $4 mouse organs by human leuke-

mic cells from children with newly diagnosed AML. Sections from the indicated SClD mouse organs show dense leukemic infiltrates. The results are repre-

i%?q sentative of leukemic SClD mice ,S-,< _,, trt .;.x, . -ti with disseminated human AML. ..-*JI?~+y;4;e$$?+;'h - G

of SClD mouse thymus (Fig I , AI and A2). The mitotic rates of leukemic cells were very high, ranging from I O to 40 per high-power field. There were 8, 12. I O , and 10 mitotic figures per 1,000 leukemic cells in thymuses from SCID mouse nos. 237 1,2383.2389, and 2487, indicating continued brisk proliferation of human AML blasts in this xeno-microenvironment. In some cases. there was an extension from the thymic mass onto the epicardium. Occurrence of histopathologically detectable disseminated leukemia was dependent on IV injection of leukemic cells: mice challenged with an innoculum transplanted under the kidney capsule did not develop overt leukemia (Table 2).

Leukemic cells from 1 of 4 patients with t(8:21) AML and




HUMAN AML IN SClD MICE 23

4 of 6 patients with inv( 16) AML caused histopathologically detectable disseminated leukemia (Table 2). Three SClD mice with disseminated leukemia (viz, SCID mouse nos. 2488,2390. and 2389 in Table 2) had massive hepatospleno- megaly secondary to leukemic involvement. Per 1.000 leukemic cells in the spleens of SClD mouse nos. 2488. 2390. and 2389. there were 6.2. and 9 mitotic figures. respectively. I n the livers of the same mice. there were 7. 2. and 8 mitotic figures per 1.000 leukemic cells. Leukemic cells from the remaining patients produced disseminated but occult leukc- min that was only detected by PCR ( i n addition to the aforc- mentioned histopnthologically detectable inliltration of SClD mouse thymus) (Tablc 2). In inliltrated BMs (Fig 1. B I and €32). ovaries (Fig I . C l and C2). and spleens (Fig I . FI and F2) of mice with overt leukemia. normal elements were replaced by sheets of AML cells. In some spleens. AML blasts were present in large subcapsular and peritrabe- cular rafts.

There were medium-size portal infiltrates (Fig I , Dl. D2. and E l ) and many small intrasinusoidal nests (Fig I . E2 and E3) in the livers. The involved kidneys showed perivascular, cortical, and pelvic infiltrates (Fig 1. GI through G3) with 2 to 7 mitotic figures per I.O()O leukemic cells. There were thick perivascular cuffs a s well ;IS subpleural and alveolar septal infiltrates in the lungs and large epicardial plaques on the right ventricle of hearts. In some mice. we found chloromas in the paraovarian and anterior mediastinal fat. Multiparame- ter flow cytometry confirmed the presence of large numbers of CD13' and/or CD33' human AML cells in BM. spleen. and liver of SClD mice with overt leukemia (data not shown). Thus. primary leukemic cells from some children with newly diagnosed AML are capable of not only engrafting but also continuously proliferating in multiple organs of SClD mice leading to organomegnly. replacement of normal elements. effacement of normal organ architecture. and detection of large numbers of leukemic cells that are in metaphase.




24 CHELSTROM ET AL

UPN 11 UPN 9 UPN 10 SClD 2375 (IV) SClD 2485 (IV) SClD 2389 (W)

' * Qw A e"@ 6 '- qo~o - @G&' Q* $ Q0(jo- c, 5-3 4, + (po+

Q 5 4 Q

Fig 2. PCR detection of human DNA in SClD mice inoculated with primary AML blasts. SClD mouse DNA was obtained from bone marrow (BM), liver (LW, spleen (SPL), brain (BR), and thymus (THY) of SClD mice challenged with primary leukemic cells from patients with newly diagnosed AML. Nonquantitative PCR amplification of a 110-bp DNA fragment (indicated by arrow) from the first exon of the human pglobin gene was performed using two 20-base oligonucleotide primers PC03 and PC04 that flank the region t o be amplified, as previously reported."'" DNA from NALM-6 pre-B ALL cell line was used as a positive control (POS CONI and PCR reactions were also performed in the absence of DNA (NEG CON). Results from eight mice selected from Table 2 are shown t o illustrate the presence of human DNA in tissues of SClD mice with overt (SCID mouse nos. 2483,2389) or occult (SCID mouse nos. 2493,2383,2307,2495,2375,2485) leukemia. The complete data analysis is shown in Table 2. No false-positive PCR signal was seen in DNA from organs of control SClD mice that were not inoculated with human leukemia cells.




HUMAN AML IN SCID MICE 25

In all SCID mice challenged with primary AML cells, including those with disseminated overt leukemia as well as those without histopathologically detectable leukemia in any organ but the thymus, human DNA was detected in DNA samples from BM, spleen, liver, brain, andor thymus by PCR amplification of a 110-bp DNA fragment from the first exon of the human ,&globin gene (Fig 2).

We have previously shown that primary leukemic cells from a significant portion of children with newly diagnosed ALL cause disseminated leukemia when injected IV into sublethally irradiated SCID mice.25 The ability of human ALL blasts to grow in SCID mice was associated with poor treatment outcome among ALL ~atients.2~ In contrast, no obvious association was noted in the present study between occurrence of leukemia in SCID mice and other presenting clinical and laboratoty features of patients from whom the cells were derived (Table 1). Long-term studies of a larger patient population are needed to carefully determine whether the occurrence of overt leukemia in SCID mice correlates with treatment outcome in pediatric AML.

The ability of primary leukemia cells from children with newly diagnosed AML to engraft and grow in SCID mice has not been previously investigated. However, a number of studies examined the growth potential of leukemic cells from adult patients in SCID Sawyers et all5 have reported that the KG1 AML cell line caused leukemia in SCID mice. However, when SCID mice were inoculated with primary leukemic cells from three relapsed AML patients and one newly diagnosed AML patient, only local growth under the kidney capsule was ob~erved.'~ None of the mice developed disseminated leukemia, and none of the mice showed a significant level of engraftment of human AML cells when challenged IV.I5 Similarly, DeLord et all9 reported that primary leukemic cells from three patients with AML failed to cause leukemia in SCID mice, although the HL-60 AML cell line caused fatal leukemia in the same model system. In contrast to the aforementioned studies, Lapidot et all4 and Cesano et a l l 6 reported that primary leukemic cells from some patients with newly diagnosed or relapsed AML are able to cause disseminated leukemia in SCID mice. Nami- kawa et alzo reported that human AML cells can proliferate in human fetal bone grafts in SCID-hu mice. However, in contrast to the studies by Lapidot et all4 and Cesano et a1,I6 AML cells were found to grow selectively in the human hematopoietic microenvironment and failed to infiltrate SCID mouse organs." Lapidot et aIz6 recently reported that a cytokine-dependent immature cell is responsible for initiating human AML after transplantation into irradiated SCID mice. In the present study, we examined the ability of cytoge- netically characterized primary blasts from children with newly diagnosed de novo AML to cause leukemia in SCID mice without administration of exogenous PIXY321 (a fu- sion protein of human granulocyte-macrophage colony-stim- ulating factor with human interleukin-3) and mast cell growth factor that were reported by Lapidot et alZ6 to be necessary for development of disseminated human AML in SCID mice. Leukemic blasts from a majority of children with newly diagnosed inv(l6) AML caused disseminated human leukemia in SCID mice. We also provide unprece- dented evidence that the SCID mouse thymic microenviron-

ment fosters the in vivo survival and growth of primary leukemic cells from children with t(8;21), inv(l6), as well as t(9; 11) carrying AML.

Clonogenic assays have been used to examine the in vitro antileukemic efficacy of new drugs against freshly isolated primary AML cells. However, in vitro clonogenic assays do not directly test the in vivo efficacy of a new agent, nor do they provide information regarding toxicity. Before clinical trials are initiated in patients, information regarding the in vivo activity and pharmacodynamic features of a potentially useful drug is desirable. The proper in vivo model also offers an opportunity to evaluate the combined toxicity and efficacy of multi-agent therapeutic regimens. The SCID mouse model system should prove particularly helpful in designing more effective treatment strategies against childhood AML.

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26 CHELSTROM ET AL

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LM Chelstrom, R Gunther, J Simon, SC Raimondi, R Krance, WM Crist and FM Uckun immunodeficiencyChildhood acute myeloid leukemia in mice with severe combined

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